Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])[CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1cc(Cl)ccn1)N1CCCC1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccnc(C(=O)N3CCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Aminophenol (122 mg, 1.12 mmol) is dissolved in DMF (3 ml) and treated with potassium-tert-butylate (131 mg, 1.16 mmol) at rt. The reaction mixture is stirred for 2 h to give a brown suspension. (4-Chloro-pyridin-2-yl)-pyrrolidin-1-yl-methanone (Stage 101.1; 236 mg, 1.12 mmol) and K2CO3 (82 mg, 0.59 mmol) are added. The reaction mixture is then stirred for 12 h at 80° C. It Is allowed to cool to rt again and the solvent is removed in vacuo. The residual brown oil is taken up in ethyl acetate and washed with brine. The organic layer is dried over MgSO4, concentrated and the residual crude product is purified by flash chromatography (SiO2; gradient CH2Cl2/MeOH 99:1 to 92:8) to give the title compound as a slightly brown solid: C16H17N3O2: M+=284.2.
Reaction SMILES: S(Cl)(Cl)=O.[N:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C@H:16]3[CH2:21][CH2:20][C@H:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]3)[O:13][N:12]=2)=[CH:7][CH:6]=1.[CH2:25](O)[CH2:26][CH3:27]>>[CH2:25]([O:23][C:22]([C@H:19]1[CH2:18][CH2:17][C@H:16]([C:14]2[O:13][N:12]=[C:11]([C:8]3[CH:9]=[CH:10][N:5]=[CH:6][CH:7]=3)[N:15]=2)[CH2:21][CH2:20]1)=[O:24])[CH2:26][CH3:27]
Reactant: CCCO
Reactant: O=C(O)[C@H]1CC[C@H](c2nc(-c3ccncc3)no2)CC1
Solvent: O=S(Cl)Cl
Product: CCCOC(=O)[C@H]1CC[C@H](c2nc(-c3ccncc3)no2)CC1

Procedure:
Thionyl chloride (11.5 μl, 0.1 mmol) was added to a solution of trans-4-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-yl)cyclohexanecarboxylic acid (Preparation 4, 22 mg, 0.08 mmol) in 1-propanol (2 ml). The mixture was heated under reflux for 2 h, cooled and the solvent removed in vacuo. The residue was dissolved in EtOAc (10 ml), washed with saturated aqueous NaHCO3 (3 ml) and brine (5 ml), then dried (MgSO4). Removal of the solvent afforded the title compound. RT=3.67 min, m/z (ES+)=316.3 [M+H]+.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[CH2:6]([CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:14][OH:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:6]([CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:14][O:15][P:1]([Cl:5])([Cl:3])=[O:2])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCC(CO)CCCCCCC
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(CCCCCCC)COP(=O)(Cl)Cl
Temperature: -10 °C
Yield: 34.7 %

Procedure:
With nitrogen substitution, 540 ml of toluene and 138.0 grams (0.9 moles) of phosphorus oxychloride were added and cooled to −10 degrees C. To this mixture, a solution of 243.5 grams (0.9 moles; 1.0 in molar ratio) of 2-heptylundecanol and 91.1 grams (0.9 moles) of triethylamine was dripped, and the mixture was reacted for 12 hours at 0 degrees C. The mixture was then heated to 25 degrees C., and a triethylamine hydrochloride was removed by filtering to obtain 1003.9 grams of a toluene solution of (2-heptylundecyl)dichlorophosphate (34.7% in concentration).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH3:30][O:31][CH2:32][CH2:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([C:36](=[O:37])[CH2:35][O:34][CH2:33][CH2:32][O:31][CH3:30])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: COCCOCC(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)COCCOC)C3)cc1

Procedure:
Compound dz was prepared according to the procedure described in Example 5 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 2-(2-methoxyethoxy)acetyl chloride. LC-MS: m/z=+513 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH:10]=[C:9]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[N:8]=[N:7][C:6]=2[N:5]([CH3:18])[C:4](=[O:19])[C:3]=1[C:20](OC)=[O:21].ClC1N=NC2N(C)C(=O)[C:33]([C:36]([O:38]C)=[O:37])=C(O)C=2C=1.[NH:42]1CCCCC1>>[OH:1][C:2]1[C:11]2[CH:10]=[C:9]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[N:8]=[N:7][C:6]=2[N:5]([CH3:18])[C:4](=[O:19])[C:3]=1[C:20]([NH:42][CH2:33][C:36]([OH:38])=[O:37])=[O:21]
Reactant: COC(=O)c1c(O)c2cc(N3CCCCC3)nnc2n(C)c1=O
Reactant: C1CCNCC1
Reactant: COC(=O)c1c(O)c2cc(Cl)nnc2n(C)c1=O
Product: Cn1c(=O)c(C(=O)NCC(=O)O)c(O)c2cc(N3CCCCC3)nnc21

Procedure:
Methyl 5-hydroxy-8-methyl-7-oxo-3-(piperidin-1-yl)-7,8-dihydropyrido[2,3-c]pyridazine-6-carboxylate. The title compound is prepared by reaction of methyl 3-chloro-5-hydroxy-8-methyl-7-oxo-7,8-dihydropyrido[2,3-c]pyridazine-6-carboxylate with piperidine according to literature procedures. Alternatively, the title compound is prepared by reaction of methyl 3-chloro-5-hydroxy-8-methyl-7-oxo-7,8-dihydropyrido[2,3-c]pyridazine-6-carboxylate with piperidine according to Method 7(a).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:16]3[CH2:18][O:19][CH2:20][CH:21]([CH3:22])[C:15]=3[N:14]=2)=[CH:8][C:4]=1[C:5](O)=[O:6])[CH3:2].Cl.[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.C(Cl)CCl>CN(C=O)C.C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([C:3]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:16]3[CH2:18][O:19][CH2:20][CH:21]([CH3:22])[C:15]=3[N:14]=2)=[CH:8][C:4]=1[C:5]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:6])[CH3:2]
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: CCc1cc(C)c(-c2nc3c([nH]2)COCC3C)cc1C(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1cc(C)c(-c2nc3c([nH]2)COCC3C)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reaction time: 8 h
Yield: 6.8 %

Procedure:
Into around-bottom flask, was placed a solution of 2-ethyl-4-methyl-5-(7-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoic acid (compound 400.3, 30 mg, 0.10 mmol, 1.0 equiv) in DMF/DCM (5/5 mL). 4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 50 mg, 0.22 mmol, 2.2 equiv), EDC (40 mg, 2.0 equiv) and 4-dimethylaminopyridine (28 mg, 2.0 equiv) were added. The resulting solution was stiffed overnight at 25° C., then quenched with water (10 mL). The mixture was extracted with ethyl acetate (3×5 mL), and the combined organic layers was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatraphy with ethyl acetate/petroleum ether (2:1) as the eluent to obtain the title compound as a light yellow solid (3.2 mg, 7%). m/z (ES+) 469 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2.Br[CH:24]([CH:32]=O)[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].CN(C)C(=O)C>O>[CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:14][C:24]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:32][N:13]=1)=[CH:8]2
Reactant: CCOC(=O)CCC(Br)C=O
Reactant: CN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)CCc1cnc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)s1
Temperature: 90 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (4.00 g), ethyl 4-bromo-5-oxopentanoate (3.80 g) and N,N-dimethylacetamide (25 mL) was stirred at 90° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (3.79 g, yield 70%) was obtained as yellow crystals from a fraction eluted with tetrahydrofuran-hexane (2:3, volume ratio). melting point 126-127° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:20][CH:19]=3)[N:9]=2)[CH2:3]1.CCN(CC)CC.[C:39](Cl)(=[O:47])[O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[C:12]([C:11]1[CH:15]=[CH:16][C:8]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:2]([NH:1][C:39](=[O:47])[O:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:3]2)=[N:9][C:10]=1[NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])=[CH:22][CH:23]=1)(=[O:13])[NH2:14]
Reactant: NC(=O)c1ccc(N2CCC[C@@H](N)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc(N2CCC[C@@H](NC(=O)Oc3ccccc3)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reaction time: 0.17 h
Yield: 51.7 %

Procedure:
To a suspension of (R)-6-(3-aminopiperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (140 mg, 0.330 mmol) and Et3N (0.069 mL, 0.495 mmol) in CH2Cl2 (3 mL) was added phenyl carbonochloridate (51.6 mg, 0.330 mmol) at 0° C. and stirred for 10 min. The reaction mixture was quenched with satd. NaHCO3, extracted with CH2Cl2, separated, and concentrated. The residue was purified (ISCO, 100% ethyl acetate, 12 g silica gel column) to obtained 93 mg of (R)-phenyl 1-(5-carbamoyl-6-(4-(morpholine-4-carbonyl)phenylamino)pyridin-2-yl)piperidin-3-ylcarbamate as a white solid. LCMS: (M+H)+=545.31. 1H NMR (400 MHz, CDCl3) δ ppm 11.20 (1H, s), 7.69 (2H, d, J=8.79 Hz), 7.50 (1H, d, J=8.79 Hz), 7.31-7.39 (4H, m, J=7.91, 7.91 Hz), 7.19 (1H, t, J=7.47 Hz), 7.08 (2H, d, J=7.47 Hz), 6.10 (1H, d, J=8.79 Hz), 5.64 (1H, s), 5.35 (1H, d, J=7.47 Hz), 5.30 (1H, s), 4.03 (1H, dd, J=12.96, 2.86 Hz), 3.78-3.91 (1H, m), 3.64 (7H, s), 3.38-3.53 (2H, m), 1.98-2.12 (1H, m), 1.76-1.87 (1H, m), 1.63-1.76 (1H, m), 1.19-1.34 (1H, m).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8]([C:10]1[N:19]([CH3:20])[C:18](=[O:21])[C:13]2=[CH:14][N:15]=[CH:16][CH:17]=[C:12]2[C:11]=1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:9].[I:39][CH3:40]>O1CCOCC1>[I-:39].[F:38][C:2]([F:37])([F:1])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:34])([F:36])[F:35])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8]([CH:10]1[NH+:19]([CH3:20])[C:18](=[O:21])[C:13]2=[CH:14][N:15]([CH3:40])[CH:16]=[CH:17][C:12]2=[C:11]1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:9]
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1c(-c2ccc(F)cc2)c2ccncc2c(=O)n1C
Reactant: CI
Solvent: C1COCCO1
Product: CN1C=CC2=C(c3ccc(F)cc3)C(C(=O)N(C)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[NH+](C)C(=O)C2=C1
Product: [I-]

Procedure:
A mixture of N-[3,5-bis(trifluoromethyl)benzyl]-4-(4-fluorophenyl)-1,2-dihydro-N, 2-dimethyl-1-oxo-3-pyrido[3,4-c]pyridinecarboxamide (Example 8) (240 mg), iodomethane (4 ml) and dioxane (4 ml) was heated for 1.5 hour under reflux. The solvent was distilled off to leave the above-titled compound as yellow crystals (303 mg), m.p.155°-158° C. (decomp.) (recrystallized from dioxane-ethyl ether).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][C:38]=1O)[C:32]([O:34][CH3:35])=[O:33].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:35][O:34][C:32](=[O:33])[C:31]1[CH:36]=[CH:37][C:38]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[C:29]([Cl:28])[CH:30]=1
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(Cl)c1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and methyl 3-chloro-4-hydroxybenzoate (commercially available) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. White foam (81%). MS (Turbo Spray): m/z=559.1 [M+H].
Reaction SMILES: C([Li])(CC)C.[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[CH3:22])=[O:12])([CH3:9])([CH3:8])[CH3:7].CON(C)[C:26](=[O:29])[CH2:27][CH3:28]>C1CCCCC1.C1COCC1>[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[CH2:22][C:26](=[O:29])[CH2:27][CH3:28])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1C
Reactant: CCC(=O)N(C)OC
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CCC(=O)Cc1c(NC(=O)OC(C)(C)C)cccc1OC
Temperature: -60 °C
Reaction time: 0.08 h

Procedure:
A solution of 140 mL (0.18 mol) of 1.3M sec-butyl lithium in cyclohexane was added slowly to N-tert-butoxycarbonyl-3-methoxy-2-methylaniline (21.3 g, 0.09 mol) in 250 mL of THF keeping the temperature below -40° C. with a dry ice-ethanol bath. The bath was removed and the temperature allowed to rise to 0° C. and then the bath replaced. After the temperature had cooled to -60° C., 18.5 g (0.18 mol) of N-methoxy-N-methylpropanamide in an equal volume of THF was added dropwise. The reaction mixture was stirred 5 minutes, the cooling bath removed and stirred an additional 18 hours. It was then poured into a mixture of 300 mL of ether and 400 mL of 0.5N HCl. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated at reduced pressure to give 25.5 g of a crude of 1-[2-(tert-butoxycarbonylamino)-6-methoxyphenyl]-2-butanone. This material was dissolved in 250 mL of methylene chloride and 50 mL of trifluoroacetic acid and stirred for a total of 17 hours. The mixture was concentrated at reduced pressure and ethyl acetate and water added to the remaining oil. The ethyl acetate was separated, washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed three times on silica eluting with 20% EtOAc/hexane to give 13.9 g of 2-ethyl-4-methoxy-1H-indole.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10](Br)[CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2].[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[N:19][CH:20]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([C:17]2[CH:18]=[N:19][CH:20]=[C:15]([F:14])[CH:16]=2)[CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1cncc(F)c1
Reactant: CCOC(=O)c1cc(Br)cc(C)n1
Product: CCOC(=O)c1cc(-c2cncc(F)c2)cc(C)n1

Procedure:
The title compound, was prepared from 4-Bromo-6-methyl-pyridine-2-carboxylic acid ethyl ester (example 1, step 4) and 5-Fluoropyridine-3-boronic acid in accordance with the general method of example 1, step 6 to yield the final compound as a light yellow oil, MS (ISP): m/e=261.2 (M+H)+.
Reaction SMILES: [C:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:14][CH3:15])=[C:8]([O:12][CH3:13])[CH:9]=2)[C:4]1=O)#[N:2].[BH4-].[Na+].ClCCl.C([OH:24])C>O>[OH:24][C:3]1([C:1]#[N:2])[CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:14][CH3:15])=[C:8]([O:12][CH3:13])[CH:9]=2)[CH2:4]1
Reactant: CCO
Reactant: COc1cc2c(cc1OC)C(=O)C(C#N)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(cc1OC)CC(O)(C#N)C2

Procedure:
2-Cyano-5,6-dimethoxy-indan-1-one (18.2 g) was suspended in ethanol (360 ml) under an atmosphere of nitrogen and treated with a solution of sodium borohydride (6.57 g) in water (25 ml) and ethanol (36 ml). After 11/2 hours dichloromethane (200 ml) was added. After a further 30 minutes the excess sodium borohydride was destroyed by the dropwise addition of acetic acid (2 ml) in dichloromethane (10 ml). The inorganic salts were filtered off and the filtrate was concentrated under reduced pressure then extracted into ethyl acetate (3×200 ml). The organic extracts were combined, washed with brine, dried over magnesium sulphate, filtered and evaporated to dryness to give 2-hydroxy-5,6-dimethoxyindane-2-carbonitrile as a yellow solid (17.1 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][CH:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:7][CH:6]=1.[C:19]1(C)[C:20]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=1.O.N1C=CC=C[CH:32]=1>>[S:25]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][CH:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:7][CH:6]=1)([C:20]1[CH:19]=[CH:24][C:23]([CH3:32])=[CH:22][CH:21]=1)(=[O:26])=[O:27]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: c1ccncc1
Reactant: O=C1NC(=O)C(Cc2ccc(OCCO)cc2)S1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Reaction time: 8 h

Procedure:
A solution of 5-[4-(2-Hydroxyethoxy)Benzyl]-2,4-Thiazolidinedione (5.34 g) in pyridine (50 ml) was cooled to below 5° C. Toluenesulphonyl chloride (3.82 g) was added portionwise to the stirred solution and the mixture was allowed to stand overnight at below 5° C. The solution was poured into water (200 ml) and extracted with dichloromethane (2×200 ml). The organic extracts washed with 5% hydrochloric acid solution and water, dried (MgSO4), filtered and evaporated under reduced pressure to give an oil which was used without further purification.
Reaction SMILES: C(O[C:4](=[O:28])[CH2:5][NH:6][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)C.[CH3:29][NH2:30]>CO>[C:22]1([S:19]([NH:18][C:14]2[CH:13]=[C:12]3[C:17](=[CH:16][CH:15]=2)[C:8]([CH2:7][NH:6][CH2:5][C:4]([NH:30][CH3:29])=[O:28])=[CH:9][CH:10]=[CH:11]3)(=[O:21])=[O:20])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN
Reactant: CCOC(=O)CNCc1cccc2cc(NS(=O)(=O)c3ccccc3)ccc12
Solvent: CO
Product: CNC(=O)CNCc1cccc2cc(NS(=O)(=O)c3ccccc3)ccc12
Temperature: 25 °C

Procedure:
[(6-Benzenesulfonylamino-naphthalen-1-ylmethyl)-amino]-acetic acid ethyl ester is added to methylamine in methanol, and the solution is stirred at room temperature, then concentrated under reduced pressure. The oil is dissolved in ethanol and 1N HCl in diethyl ether is added to precipitate 2-[(6-benzenesulfonyl-naphthalen-1-ylmethyl)-amino]-N-methyl-acetamide as a hydrochloride salt.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C1C(=O)N([Br:25])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([C:6]([C:5]2[CH:4]=[CH:3][C:2]([CH2:1][Br:25])=[CH:17][CH:16]=2)=[O:7])=[CH:9][CH:10]=1)#[N:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)c2ccc(C#N)cc2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Temperature: 25 °C
Yield: 70.3 %

Procedure:
Heat a mixture of 4-(4-methyl-benzoyl)-benzonitrile (300 mg, 1.356 mmol), NBS (386 mg, 2.169 mmol), and AIBN (22 mg, 0.136 mmol) in carbon tetrachloride (10 mL) for 14 h at reflux. Add additional NBS (121 mg) and AIBN (11 mg) and reflux the mixture for 3 h. Cool the reaction mixture to ambient temperature and filter the mixture. Concentrate the filtrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting sequentially with hexane and hexane/EtOAc (9:1) to provide the title compound as a solid (286 mg, 70%). GC-MS m/z: 300 (M+).
Reaction SMILES: C([O:8][C:9]1[CH:38]=[CH:37][CH:36]=[CH:35][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:34])[CH2:19][NH:20][C:21]([C:23]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:25][N:24]=2)=[O:22])[CH2:14][CH2:13]1)C1C=CC=CC=1.Cl.C(OOC1C=CC=CC=1NC1CCNCC1)C1C=CC=CC=1>CO.O.[Pd]>[OH:8][C:9]1[CH:38]=[CH:37][CH:36]=[CH:35][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18](=[O:34])[CH2:19][NH:20][C:21]([C:23]2[CH:27]=[C:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[NH:25][N:24]=2)=[O:22])[CH2:16][CH2:17]1
Reactant: O=C(NCC(=O)N1CCC(Oc2ccccc2OCc2ccccc2)CC1)c1cc(-c2ccccc2)[nH]n1
Agent: [Pd]
Agent: Cl
Agent: c1ccc(COOc2ccccc2NC2CCNCC2)cc1
Solvent: O
Solvent: CO
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2O)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 2 h
Yield: 71.5 %

Procedure:
10% Pd/C (10 mg) was added to a stirred solution of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-benzyloxy-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide (prepared from Intermediate 30 and (2-benzyloxyoxy-phenyl)-piperidin-4-yl-amine hydrochloride which was prepared according to the method used for the synthesis of Intermediate 15) (100 mg, 0.2 mmol) in a mixture of MeOH:H2O (1:1, 10 mL) under inert atmosphere and stirring was continued under H2 gas atmosphere for 2 hr. The reaction mixture was filtered through celite. The filtrate collected was concentrated under reduced pressure to afford the residue. The residue was purified by preparative HPLC to afford 60 mg (71.5% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-hydroxy-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 421.8, 96.21%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (b, 1H), 8.9 (b, 1H), 8.2 (b, 1H), 7.8 (m, 2H), 7.5 (m, 3H), 7.2 (s, 1H), 7.0 (d, 1H), 6.8 (m, 3H), 4.5 (m, 1H), 4.2 (m, 2H), 3.8 (m, 2H), 3.3 (m, 2H), 1.9 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH3:11])[C:8](O)=O)=[CH:4][CH:3]=1.[NH2:14][NH:15][C:16]([NH2:18])=[S:17].P(Cl)(Cl)(Cl)=O>O1CCOCC1>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([C:8]2[S:17][C:16]([NH2:18])=[N:15][N:14]=2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(Oc1ccc(Cl)cc1)C(=O)O
Reactant: NNC(N)=S
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(Oc1ccc(Cl)cc1)c1nnc(N)s1
Reaction time: 16 h

Procedure:
Into a 100 milliliter, 3-neck flask adapted with a Claisen adaptor, paddle stirrer, thermometer, an addition funnel and condensor, was charged with 10.0 grams (0.050 mole) of 2-(4-chlorophenoxy)propanoic acid, (4.6 grams, 0.050 mole) of thiosemicarbazide and 30 ml. of dioxane. The slurry was heated to 90 degrees centigrade and the addition funnel was charged with phosphorous oxychloride (POCl3). The POCl3 (8.4 gram, 0.055 mole) was slowly added (for 30 minutes) while maintaining the temperature within 85-90 degrees centigrade. The resulting mixture was refluxed for 75 minutes and stood at ambient temperature for 16 hours. The flask was evacuated by using a water aspirator to remove volatiles (HCl, POCl3 and some dioxane) at sixty degrees centigrade and then the solution was cooled. Fifty (50) milliliters of water was added and 50 percent solution of NaOH was also added until the pH of the solution was 10; a solid precipitate formed. The solid precipitate was filtered off, washed with water, then dried in a vacuum oven at 70 degrees centigrade to white crystals which were recrystallized from the minimum amount of H2O/ethanol mixture, filtered and then dried in a vacuum oven at 80 degrees centigrade to white crystals of 5-[1-(4-chlorophenoxy) ethyl]-2-amino-1,3,4-thiadiazole. (Melting point 162-166 degrees centigrade).